First report of an intravenous and oral glycoprotein IIb/IIIa inhibitor (RPR 109891) in patients with recent acute coronary syndromes

Results of the TIMI 15A and 15B trials

Robert P. Giugliano, Carolyn H. McCabe, Rafael F. Sequeira, Martin J. Frey, Timothy D. Henry, Robert N. Piana, Jean Francois Tamby, Bradford K. Jensen, Sylvain B. Nicolas, Lisa K. Jennings, Robert J. Wise, Eugene Braunwald

Research output: Contribution to journalArticle

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Abstract

Background: RPR 109891 is a modified tetrapeptide glycoprotein IIb/IIIa inhibitor available in intravenous and oral formulations. Two phase II dose- ranging studies were performed to investigate pharmacodynamics and safety in acute coronary syndromes. Methods: The Thrombolysis In Myocardial Infarction (TIMI) 15A trial was a randomized, open-label, study of RPR 109891 administered intravenously for 24 to 96 hours in 91 patients. TIMI15B was a randomized, double-blind comparison of intravenous RPR 109891 plus 4 weeks of oral RPR 109891 (n = 142) compared with placebo (n = 50). Results: Intravenous RPR 109891 exhibited a dose-response inhibition of platelet aggregation; mean inhibition after a bolus ranged from 53% to 92%, and at steady state 49% to 98%. Oral RPR 109891 demonstrated less platelet inhibition (peaks, range 48% to 59%; troughs, range 18% to 39%). Mean glycoprotein IIb/IIIa receptor occupancy and platelet inhibition were highly correlated (r = 0.82, 95% confidence interval 0.74-0.88). There were trends for increased major hemorrhage (10% vs 6%, P = .57), thrombocytopenia <90,000 cells/mm3 (13% vs 4%, P = .11), and profound thrombocytopenia <20,000 (3.5% vs 0%, P = .33) with intravenous plus oral RPR 109891 compared with placebo. In 3 of 5 cases of profound thrombocytopenia, RPR 109891 had been interrupted because of bypass surgery, and a precipitous fall in platelet count occurred after the first postoperative oral dose. Conclusions: Intravenous RPR 109891 is a potent, predictable, dose-related platelet inhibitor. Oral RPR 109891 (≤600 mg/d) achieves moderate platelet inhibition. Interrupted glycoprotein IIb/IIIa blockade may be associated with a higher risk of profound thrombocytopenia and deserves closer examination in future studies.

Original languageEnglish
Pages (from-to)81-93
Number of pages13
JournalAmerican Heart Journal
Volume140
Issue number1
DOIs
StatePublished - Jul 1 2000
Externally publishedYes

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Platelet Glycoprotein GPIIb-IIIa Complex
Acute Coronary Syndrome
Thrombocytopenia
Myocardial Infarction
Blood Platelets
Placebos
Platelet Aggregation Inhibitors
Platelet Count
Platelet Aggregation
Confidence Intervals
Hemorrhage
Safety

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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First report of an intravenous and oral glycoprotein IIb/IIIa inhibitor (RPR 109891) in patients with recent acute coronary syndromes : Results of the TIMI 15A and 15B trials. / Giugliano, Robert P.; McCabe, Carolyn H.; Sequeira, Rafael F.; Frey, Martin J.; Henry, Timothy D.; Piana, Robert N.; Tamby, Jean Francois; Jensen, Bradford K.; Nicolas, Sylvain B.; Jennings, Lisa K.; Wise, Robert J.; Braunwald, Eugene.

In: American Heart Journal, Vol. 140, No. 1, 01.07.2000, p. 81-93.

Research output: Contribution to journalArticle

Giugliano, RP, McCabe, CH, Sequeira, RF, Frey, MJ, Henry, TD, Piana, RN, Tamby, JF, Jensen, BK, Nicolas, SB, Jennings, LK, Wise, RJ & Braunwald, E 2000, 'First report of an intravenous and oral glycoprotein IIb/IIIa inhibitor (RPR 109891) in patients with recent acute coronary syndromes: Results of the TIMI 15A and 15B trials', American Heart Journal, vol. 140, no. 1, pp. 81-93. https://doi.org/10.1067/mhj.2000.107172
Giugliano, Robert P. ; McCabe, Carolyn H. ; Sequeira, Rafael F. ; Frey, Martin J. ; Henry, Timothy D. ; Piana, Robert N. ; Tamby, Jean Francois ; Jensen, Bradford K. ; Nicolas, Sylvain B. ; Jennings, Lisa K. ; Wise, Robert J. ; Braunwald, Eugene. / First report of an intravenous and oral glycoprotein IIb/IIIa inhibitor (RPR 109891) in patients with recent acute coronary syndromes : Results of the TIMI 15A and 15B trials. In: American Heart Journal. 2000 ; Vol. 140, No. 1. pp. 81-93.
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abstract = "Background: RPR 109891 is a modified tetrapeptide glycoprotein IIb/IIIa inhibitor available in intravenous and oral formulations. Two phase II dose- ranging studies were performed to investigate pharmacodynamics and safety in acute coronary syndromes. Methods: The Thrombolysis In Myocardial Infarction (TIMI) 15A trial was a randomized, open-label, study of RPR 109891 administered intravenously for 24 to 96 hours in 91 patients. TIMI15B was a randomized, double-blind comparison of intravenous RPR 109891 plus 4 weeks of oral RPR 109891 (n = 142) compared with placebo (n = 50). Results: Intravenous RPR 109891 exhibited a dose-response inhibition of platelet aggregation; mean inhibition after a bolus ranged from 53{\%} to 92{\%}, and at steady state 49{\%} to 98{\%}. Oral RPR 109891 demonstrated less platelet inhibition (peaks, range 48{\%} to 59{\%}; troughs, range 18{\%} to 39{\%}). Mean glycoprotein IIb/IIIa receptor occupancy and platelet inhibition were highly correlated (r = 0.82, 95{\%} confidence interval 0.74-0.88). There were trends for increased major hemorrhage (10{\%} vs 6{\%}, P = .57), thrombocytopenia <90,000 cells/mm3 (13{\%} vs 4{\%}, P = .11), and profound thrombocytopenia <20,000 (3.5{\%} vs 0{\%}, P = .33) with intravenous plus oral RPR 109891 compared with placebo. In 3 of 5 cases of profound thrombocytopenia, RPR 109891 had been interrupted because of bypass surgery, and a precipitous fall in platelet count occurred after the first postoperative oral dose. Conclusions: Intravenous RPR 109891 is a potent, predictable, dose-related platelet inhibitor. Oral RPR 109891 (≤600 mg/d) achieves moderate platelet inhibition. Interrupted glycoprotein IIb/IIIa blockade may be associated with a higher risk of profound thrombocytopenia and deserves closer examination in future studies.",
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T1 - First report of an intravenous and oral glycoprotein IIb/IIIa inhibitor (RPR 109891) in patients with recent acute coronary syndromes

T2 - Results of the TIMI 15A and 15B trials

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AU - McCabe, Carolyn H.

AU - Sequeira, Rafael F.

AU - Frey, Martin J.

AU - Henry, Timothy D.

AU - Piana, Robert N.

AU - Tamby, Jean Francois

AU - Jensen, Bradford K.

AU - Nicolas, Sylvain B.

AU - Jennings, Lisa K.

AU - Wise, Robert J.

AU - Braunwald, Eugene

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N2 - Background: RPR 109891 is a modified tetrapeptide glycoprotein IIb/IIIa inhibitor available in intravenous and oral formulations. Two phase II dose- ranging studies were performed to investigate pharmacodynamics and safety in acute coronary syndromes. Methods: The Thrombolysis In Myocardial Infarction (TIMI) 15A trial was a randomized, open-label, study of RPR 109891 administered intravenously for 24 to 96 hours in 91 patients. TIMI15B was a randomized, double-blind comparison of intravenous RPR 109891 plus 4 weeks of oral RPR 109891 (n = 142) compared with placebo (n = 50). Results: Intravenous RPR 109891 exhibited a dose-response inhibition of platelet aggregation; mean inhibition after a bolus ranged from 53% to 92%, and at steady state 49% to 98%. Oral RPR 109891 demonstrated less platelet inhibition (peaks, range 48% to 59%; troughs, range 18% to 39%). Mean glycoprotein IIb/IIIa receptor occupancy and platelet inhibition were highly correlated (r = 0.82, 95% confidence interval 0.74-0.88). There were trends for increased major hemorrhage (10% vs 6%, P = .57), thrombocytopenia <90,000 cells/mm3 (13% vs 4%, P = .11), and profound thrombocytopenia <20,000 (3.5% vs 0%, P = .33) with intravenous plus oral RPR 109891 compared with placebo. In 3 of 5 cases of profound thrombocytopenia, RPR 109891 had been interrupted because of bypass surgery, and a precipitous fall in platelet count occurred after the first postoperative oral dose. Conclusions: Intravenous RPR 109891 is a potent, predictable, dose-related platelet inhibitor. Oral RPR 109891 (≤600 mg/d) achieves moderate platelet inhibition. Interrupted glycoprotein IIb/IIIa blockade may be associated with a higher risk of profound thrombocytopenia and deserves closer examination in future studies.

AB - Background: RPR 109891 is a modified tetrapeptide glycoprotein IIb/IIIa inhibitor available in intravenous and oral formulations. Two phase II dose- ranging studies were performed to investigate pharmacodynamics and safety in acute coronary syndromes. Methods: The Thrombolysis In Myocardial Infarction (TIMI) 15A trial was a randomized, open-label, study of RPR 109891 administered intravenously for 24 to 96 hours in 91 patients. TIMI15B was a randomized, double-blind comparison of intravenous RPR 109891 plus 4 weeks of oral RPR 109891 (n = 142) compared with placebo (n = 50). Results: Intravenous RPR 109891 exhibited a dose-response inhibition of platelet aggregation; mean inhibition after a bolus ranged from 53% to 92%, and at steady state 49% to 98%. Oral RPR 109891 demonstrated less platelet inhibition (peaks, range 48% to 59%; troughs, range 18% to 39%). Mean glycoprotein IIb/IIIa receptor occupancy and platelet inhibition were highly correlated (r = 0.82, 95% confidence interval 0.74-0.88). There were trends for increased major hemorrhage (10% vs 6%, P = .57), thrombocytopenia <90,000 cells/mm3 (13% vs 4%, P = .11), and profound thrombocytopenia <20,000 (3.5% vs 0%, P = .33) with intravenous plus oral RPR 109891 compared with placebo. In 3 of 5 cases of profound thrombocytopenia, RPR 109891 had been interrupted because of bypass surgery, and a precipitous fall in platelet count occurred after the first postoperative oral dose. Conclusions: Intravenous RPR 109891 is a potent, predictable, dose-related platelet inhibitor. Oral RPR 109891 (≤600 mg/d) achieves moderate platelet inhibition. Interrupted glycoprotein IIb/IIIa blockade may be associated with a higher risk of profound thrombocytopenia and deserves closer examination in future studies.

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